Increasingly recognized as a health burden of global proportions, depression is especially devastating in the context of medical illness. Indeed, depression increases morbidity and hastens mortality across a range of medical disorders. Recent conceptual developments regarding the pathophysiology of depression in the medically ill have focused on the potential role of immune activation/inflammation and the associated release of proinflammatory cytokines. Proinflammatory cytokines induce symptoms of sickness that overlap with major depression and induce the production and release of central nervous system (CNS) corticotropin-releasing hormone (CRH), which is believed to be a key mediator of depression. The long term objective of this R01 application (the Pl's first R01 application) is to further understand the potential role of cytokine-induced CRH in the development of depression in the medically ill. As a model system, we propose to study patients receiving the cytokine, interferon-alpha (IFN-alpha) for the treatment of hepatitis C virus infection (HCV). IFN-alpha potently induces proinflammatory cytokines and leads to depressive symptoms in 30-50% of patients, depending on the dose. In animals, IFN-alpha stimulates the production and release of CRH within the CNS, and blocking CNS CRH attenuates IFN-alpha induced sickness behavior. Our preliminary data indicates that patients who demonstrate hyperactivity in CRH-mediated neuroendocrine pathways in response to a first dose of IFN-alpha have an increased risk of developing depression during IFN-alpha therapy. We have also shown that early life stress (ELS) is associated with sensitization of CRH pathways, indicating a potential link between stress sensitivity and the risk for developing depression during cytokine therapy. We hypothesize that a) patients who demonstrate CRH hyperacitvity in response to an immune challenge will also demonstrate hyperactivity in response to a psychological stressor, and b) hyperactivity to both types of stressors will be associated with the development of IFN-alpha induced depression. Moreover, we anticipate that patients with a history of ELS, current life stress and/or a personal or family history of depression will demonstrate increased CRH reactivity to immunological and psychological stressors. To test these hypotheses, 50 subjects receiving IFN-alpha/ribavirin for HCV will be evaluated for neuroendocrine responses to an immune challenge (first dose of IFN-alpha) and a laboratory psychological stressor (Trier Social Stress Test). Depressive symptoms will be evaluated at baseline and during 12 weeks of treatment with IFN-alpha/ribavirin. All assessments will be conducted in parallel in 25 HCV+ patients randomized to postpone IFN-alpha during the study period (HCV+ controls). Results from these studies will provide important new data on CRH as a potential vulnerability factor for depression in the medically ill and will establish a foundation for developing novel treatment strategies for depression in these patients.